One of the curious things about Neuroendocrine Cancer (NET Cancer) is that it can exhibit one or more vague symptoms collectively known as a ‘syndrome’. Syndrome is an apt word to describe these complications as the most general meaning in medical terms is “
Most people think of Carcinoid Syndrome when they discuss NET Cancer but there are in actual fact, several associated syndromes depending on the location and type of NET Cancer. Not everyone will have a ‘syndrome’ in addition to their tumours. Take the most common form of NET Cancer as an example – statistics vary from source to source but it is estimated that around a 30-45% of all midgut NET Cancer patients will present with metastatic disease and around a third of those (∼10-15% of all midgut) will exhibit Carcinoid Syndrome indicating their tumours are functional (secreting excess hormones, particularly serotonin). It follows that Carcinoid Syndrome itself is not that common and it could be the same with other types of NET Cancer (even though it can appear more prevalent on forums). In fact a large proportion of Pancreatic NETs are non-functional at diagnosis.
These tumours and associated syndromes are treatable for most but the difficult part can be arriving at a diagnosis. Moreover, without a syndrome, some of these tumours can be silently growing and as they grow slowly, the ‘silence’ can go on for some years. Even with a syndrome, the root cause can remain disguised as the symptoms are similar to many day-to-day illnesses, again the reason for the title of this blog. Curiously, the lack of a syndrome can sometimes lead to an even later presentation and the consequences that arise (i.e. no signs to aid a diagnosis). There can be the odd exception but in general terms, NETs are either functional (with a syndrome) or non-functional (no syndrome).
The ISI Book on Neuroendocrine Tumors 2016 (Woltering et al) confirms there are a number of syndromes associated directly and indirectly with NET Cancer. For example Carcinoid, Gastrinoma, Insulinoma, Somatostatinoma, Glucagonoma, and watery diarrhea (WDHA) (VIPoma) are described as individual syndromes according to their secretory hormones and peptides. The referenced publication expands on this list to aid diagnoses by including common presentations, associated tumour types and locations and the offending secreting hormones. You can see why NET Cancer is a diagnostic challenge!
Major NET Syndromes – (information mainly taken from the ISI Book on NETs):
Carcinoid – a syndrome connected with conventional carcinoid locations (small intestine, lung, stomach, appendix etc). Type 2 Gastric NET can be associated with Zollinger-Ellinson Syndrome (ZES) see also below.
Insulin – Insulinoma (Whipple’s Triad) – Whipple’s Triad is the classic description of insulinoma which includes symptoms of hypoglycemia with a low blood glucose concentration relieved by the ingestion of glucose. These tumours can be located anywhere within the pancreas in the cells that make insulin. Insulin is a hormone that controls the amount of glucose (sugar) in the blood. It moves glucose into the cells, where it can be used by the body for energy. Insulinomas are usually slow-growing tumors that rarely spread. Some of these tumours will be associated with MEN1.
Gastrin – Gastrinoma A tumour that forms in cells that make gastrin. Gastrin is a hormone that causes the stomach to release an acid that helps digest food. Both gastrin and stomach acid are increased by gastrinomas. When increased stomach acid, stomach ulcers and diarrhea are caused by a tumour that makes gastrin, it is called Zollinger-Ellinson Syndrome (see also below). Gastrinoma usually forms in the head of the pancreas. Some of these tumours may be associated with MEN1 syndrome.
Glucagon – Glucagonoma. A tumour that forms in cells that make make glucagon. Glucagon is a hormone that increases the amount of glucose in the blood. It causes the liver to break down glycogen. Too much glucagon causes hyperglycemia (high blood sugar). A glucagonoma usually forms in the tail of the pancreas. Some of these tumours may be associated with MEN1 syndrome. See also Sweet’s Syndrome below.
Pancreatic Polypeptide (PP) – PPoma. A complicated one and not too much information (even in the ISI book). However, it’s the third most common type of islet cell tumour (i.e. pNET). The function of pancreatic polypeptide is not completely understood. Patients present with weight loss, jaundice, and abdominal pain. The diagnosis is confirmed by pancreatic polypeptide levels > 300 pg/ml. Some of these tumours may be associated with MEN1 syndrome.
WDHA – Associated with VIPoma. The syndrome of watery diarrhea, hypokalemia (potassium deficiency), and achlorhydria (absence of hydrochloric acid in gastric secretions). VIPomas make vasoactive intestinal peptide (VIP). VIPoma may also be called Verner-Morrison syndrome.
Somatostatin – Somatostatinoma is a very rare NET, with an incidence of one in 40 million persons. These tumours arise from the delta cells in the pancreas, although these cells can also be present in duodenal tissue where 40% of the tumours occur. Somatostatin is a naturally occurring peptide that inhibits the function of almost all gut hormones (author’s note – this should give you an appreciation of how somatostatin analogues tackle associated syndromes but gives you certain side effects as a result!)
Hedinger Syndrome – the technical term for Carcinoid Heart Disease.
MEN1 – Mainly involved the 3 Ps, Pituitary, Pancreas and Parathyroid. The pituitary tumours are primarily Prolactinomas, the pancreatic tumours are mainly PPomas, Gastrinomas and Insulinoma. Many also have association with Zollinger-Ellinson syndrome (ZES). Read more here. Previously known as Wermer Syndrome.
Zollinger-Ellinson Syndrome (ZES). This is a rare condition in which one or more tumours form in the pancreas, the upper part of the duodenum or the stomach. These tumours secrete large amounts of the hormone gastrin, which causes your stomach to produce too much acid. The excess acid can lead to peptic ulcers, in addition to diarrhea and other symptoms. Associated with Gastrinoma (pNET) and Type 2 Gastric NETs.
Cushing’s – also known as hypercortisolism. A collection of symptoms caused by very high levels of a hormone called cortisol in the body. Associated with AdrenoCorticoTropic Hormone (ACTH). In Cushing’s disease, oversecretion of pituitary ACTH induces bilateral adrenal hyperplasia. This results in excess production of cortisol, adrenal androgens, and 11-deoxycorticosterone. Cushing’s disease, a subset of Cushing’s syndrome, is due to a pituitary corticotroph adenoma and results in a partial resistance to the suppression of ACTH by cortisol so that secretion is unrestrained. In contrast, causes of Cushing’s syndrome may include the following:
• Adrenal adenoma or carcinoma arise spontaneously. ACTH levels are undetectable.
• Non-pituitary (ectopic) tumours produce ACTH. They most frequently originate in the thorax and are highly aggressive small cell carcinomas of the lung or slow- growing bronchial or thymic carcinoid tumours. Some produce corticotropin- releasing hormone (CRH) instead, which stimulates pituitary ACTH secretion and can therefore mimic a pituitary tumour.
• Other causes include carcinoid tumours of the gastric, pancreatic, and intestinal organs; Pheochromocytomas, and MCT.
The hallmark of Cushing’s syndrome is that ACTH levels are partially resistant to suppression with dexamethasone, even at very high doses. Some MEN patients with pituitary tumours may have Cushing’s Syndrome.
Sweet’s – Dermatitis/rash associated with Glucagonomas. Not to be confused with Pellagra.
There are many other less known syndromes that appear to be directly or indirectly connected with Neuroendocrine Tumours and I may update this blog if I discover they are more prevalent than I think.
As for my own experience of syndromes, I did once show symptoms of the most common NET syndrome (currently known as Carcinoid syndrome) where the key symptoms are flushing, diarrhea and wheezing. You can see why those symptoms are frequently and easily confused with other conditions. If you have a similar diagnosis, y
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